Hyaluronidase-trigger nanocarriers for targeted delivery of anti-liver cancer compound

Chemotherapy is recognized as one of the significant treatment methods for liver cancer. The compound celastrol (CSL) could effectively inhibit the proliferation, migration, and invasion of liver cancer cells, which is regarded as a promising candidate to become a mainstream anti-liver cancer drug. However, the application of CSL in liver cancer chemotherapy is limited due to its systemic toxicity, poor water solubility, multidrug resistance, premature degradation, and lack of tumor targeting. Meanwhile, in order to comply with the current concept of precision medicine, precisely targeted delivery of the anti-liver compound CSL was desired. This paper takes into account that liver cancer cells were equipped with hyaluronic acid (HA) receptors (CD44) on their surface and overexpressed. Hyaluronidase (HAase) capable of degrading HA, HAase-responsive nanocarriers (NCs), named HA/(MI)₇-β-CD NCs, were prepared based on the electrostatic interaction between HA and imidazole moieties modified β-cyclodextrin (MI)₇-β-CD. HA/(MI)₇-β-CD NCs showed disassembly properties under HAase stimuli, which was utilized to trap, deliver, and the controllable release of the anti-liver cancer compound CSL. Furthermore, cytotoxicity assay experiments revealed that CSL-trapped HA/(MI)₇-β-CD NCs not only reduced cytotoxicity for normal cells but also effectively inhibited the survival for five tumor cells, and even the apoptotic effect of CSL-trapped NCs with a concentration of 5 μg mL^-1 on tumor cells (SMMC-7721) was consistent with free CSL. Cell uptake experiments demonstrated HA/(MI)₇-β-CD NCs possessed the capability of targeted drug delivery to cancerous cells. HA/(MI)₇-β-CD NCs exhibited site-specific and controllable release performance, which is anticipated to proceed further in precision-targeted drug delivery systems.